SUMMARY The objective of this proposal is to elucidate the cellular and molecular basis of retinal and cerebellar degeneration in Spinocerebellar ataxia type 7 (SCA7). A theme in inherited retinal degenerations and cerebellar ataxias is an exquisite vulnerability to DNA damage. Nuclear pore complexes are required for the transport of proteins that contribute to efficient DNA repair. We found transcription factor binding site analysis of SCA7 down-regulated genes revealed putative binding sites for peroxisome proliferator-activated receptors (PPARs), which are known pathway targets of Sirtuin-1 (Sirt1), a NAD+-dependent deacetylase implicated in lifespan extension and neuroprotection. We documented significant reductions in NAD+ levels in SCA7 brains and found evidence for impaired DNA repair, a process which relies upon normal nuclear import of translated proteins that are involved in sensing DNA damage and mediating DNA repair. Studies from a number of labs, including our own research group, have now shown that nucleocytoplasmic transport is impaired in age-related neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Huntington?s disease (HD). We hypothesize that polyglutamine-expanded ataxin 7 disrupts nucleocytoplasmic transport in SCA7 by interfering with the stability and/or function of nuclear pore complex proteins, such as nucleoporins (NUPs), and nucleocytoplasmic transport factors such as importins/exportins. Indeed, this hypothesis is supported by our previously published work documenting that ataxin-7 possesses both a functional nuclear localization signal (NLS) and nuclear export signal (NES), and is thus constantly trafficking into and out of the nucleus. The recent discovery of nuclear membrane pathology and mislocalization of nucleocytoplasmic transport proteins, such as Ran, RanGap1, Pom121, Xpo1, NxF1 and RanBP2, has highlighted the potential importance of nucleocytoplasmic transport in neurodegenerative disease pathogenesis. This proposed research will greatly advance our understanding of SCA7 pathology, and will evaluate the role of altered nuclear membrane function and dysregulated nucleocytoplasmic transport in retinal health and degeneration. Our specific aims will be to: 1) Determine if aggregates of polyQ-expanded ataxin-7 result in aberrant localization of nuclear pore proteins and/or nucleocytoplasmic transport regulatory factors in SCA7 model mice, and 2) Examine the status of nucleocytoplasmic transport in neurons from SCA7 mice and human patients to determine if nucleocytoplasmic transport is impaired in SCA7.